Osteoarthritis (OA) is one of the most disabling diseases in developed countries. The prevalence of OA is estimated to one in ten men and one in five women aged over 60 years worldwide. As such, the disease accounts for considerable health care expenditure and therefore represents a significant socio-economic burden. To date, no disease modifying treatment is available. Current treatment is therefore entirely symptomatic up to the point when total joint replacement may be indicated.
In spite of this significant importance for the health system, the causes of OA remain unclear to date and effective preventative measures furthermore remain a distant aim. A reduction in the joint gap (caused by destruction of the joint cartilage), together with changes in the subchondral bone and osteophyte formation, are the radiological characteristics of the disease. For the patient, however, pain (load-dependent and nocturnal rest pain) with subsequent function impairments are to the fore. It is also these which force the patient into social isolation with corresponding secondary diseases.
The term osteoarthritis according to an unofficial definition denotes “joint wear” which exceeds the usual extent for the age. The causes are regarded as being excessive load (for example increased body weight), connatal or traumatic causes, such as malposition of the joint, or also bone deformations due to bone diseases, such as osteoporosis. Osteoarthritis can likewise arise as a consequence of another disease, for example joint inflammation (arthritis) (secondary osteoarthritis), or accompany overload-induced effusion (secondary inflammation reaction) (activated osteoarthritis). The Anglo-American specialist literature differentiates between osteoarthritis (OA), in which the destruction of the joint surfaces can probably be attributed principally to the effects of load, and arthritis (rheumatoid arthritis, RA), in which joint degeneration due to an inflammatory component is to the fore.
In principle, osteoarthritis is also differentiated according to its cause. Arthrosis alcaptonurica is based on increased deposition of homogentisic acid in joints in the case of previously existing alcaptonuria. In the case of haemophilic arthrosis, regular intra-articular bleeding occurs in the case of haemophilia (haemophilic joint). Arthrosis urica is caused by the mechanical influence of urate crystals (uric acid) on the healthy cartilage (Pschyrembel W. et al.: Klinisches Wörterbuch, Verlag Walter de Gruyter & Co, 253rd Edition, 1977).
The classical cause of osteoarthritis is dysplasia of joints. Using the example of the hip, it becomes clear that the zone with the greatest mechanical stress in the case of a physiological hip position represents a significantly larger area than in the case of a dysplastic hip. However, the stresses caused by the forces acting on the joint are substantially independent of the joint shape. They are essentially distributed over the main stress zone(s). A greater pressure will thus arise in the case of a relatively small zone than in the case of a larger one. The biomechanical pressure on the joint cartilage is thus greater in the case of a dysplastic hip than in the case of a physiological hip position. This rule is generally regarded as the cause of the increased occurrence of arthritic changes in supporting joints which differ from the ideal anatomical shape.
If the consequences of an injury are responsible for premature wear, the term post-traumatic arthrosis is used. Further causes of secondary arthrosis or osteoarthritis that are being discussed are mechanical, inflammatory, metabolic, chemical (quinolones), trophic, hormonal, neurological and genetic reasons. In most cases, however, the diagnosis given is idiopathic arthrosis, by which the doctor means an apparent absence of a causal disease (H. I. Roach and S. Tilley, Bone and Osteoarthritis, F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).
Medicinal causes of osteoarthritis can be, for example, antibiotics of the gyrase inhibitor type (fluoroquinolones, such as ciprofloxacin, levofloxacin). These medicaments result in complexing of magnesium ions in poorly vascularised tissues (hyaline joint cartilage, tendon tissue), which has the consequence that irreversible damage occurs to connective tissue. This damage is generally more pronounced in the growth phase in children and juveniles. Tendinopathies and arthropathies are known side effects of this class of medicaments. In adults, these antibiotics result in accelerated physiological degradation of the hyaline joint cartilage according to information from independent pharmacologists and rheumatologists (Menschik M. et al., Antimicrob. Agents Chemother. 41, pp. 2562-2565, 1997; Egerbacher M. et al., Arch. Toxicol. 73, pp. 557-563, 2000; Chang H. et al., Scand. J. Infect. Dis. 28, pp. 641-643, 1996; Chaslerie A. et al., Therapie 47, p. 80, 1992). Extended treatment with phenprocoumone can also favour arthrosis by decreasing bone density in the case of stresses of the joint internal structure.
Besides age, known risk factors for osteoarthrosis are mechanical overload, (micro)traumas, joint destabilisation caused by loss of the securing mechanisms, and genetic factors. However, neither the occurrence nor possible interventions have been fully explained (H. I. Roach and S. Tilley, Bone and Osteoarthritis, F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).
In a joint affected by osteoarthritis, the content of nitrogen monoxide is increased in some cases. A similar situation has been observed due to high mechanical irritation of cartilage tissue (Das P. et al., Journal of Orthopaedic Research 15, pp. 87-93, 1997; Farrell A. J. et al., Annals of the Rheumatic Diseases 51, pp. 1219-1222, 1992; Fermor B. et al., Journal of Orthopaedic Research 19, pp. 729-737, 2001), whereas moderate mechanical stimulation tends to have a positive effect. The action of mechanical forces is thus causally involved in the progress of osteoarthritis (Liu X. et al., Biorheology 43, pp. 183-190, 2006).
In principle, osteoarthritis therapy follows two aims: firstly freedom from pain under normal load and secondly the prevention of mechanical restrictions or changes in a joint. These aims cannot be achieved in the long term by pain treatment as a purely symptomatic therapy approach, since this cannot halt the progress of the disease. If the latter is to be achieved, the cartilage destruction must be stopped. Since the joint cartilage in adult patients cannot regenerate, the elimination of pathogenetic factors, such as joint dysplasia or malpositions, which result in increased point pressure on the joint cartilage, is in addition enormously important.
Finally, it is attempted to prevent or stop the degeneration processes in the cartilage tissue with the aid of medicaments.
An essential factor for the functioning state and thus the resistance of the joint cartilage to stress is the extracellular matrix, which primarily consists of collagens, proteoglycans and water. The enzymes involved in degradation of the extracellular matrix include, in particular the metalloproteases, aggrecanases and cathepsin enzymes.
Aggrecan is a main proteoglycan in cartilage, and decomposition of its core protein by protease is one of the early signs of a joint disorder associated with arthrodial cartilage destruction, such as rheumatoid arthritis and osteoarthritis. This process of decomposition leading to the cartilage destruction begins with the disappearance of aggrecan on the surface of cartilage, and progresses to the decomposition of collagen type II fiber (Sandy J. D. et al., J. Clin. Invest. 89, 1512-1516, 1992; Lohmander L. S. et al., Arthritis Rheum. 36, 1214-1222, 1993).
MMPs (matrix metalloproteinases) that cleave Asn 341-Phe 342 and aggrecanase that cleaves Glu 373-Ala 374 are known as enzymes involved in this decomposition of aggrecan, and both are metal-pro/eases having zinc in the catalytic active center. The latter was determined to be ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) in 1999. ADAMTS 1 to 20 have been identified so far, and ADAMTS 4 and 5 to aggrecanase-1 and aggrecanase-2, respectively (Abbaszade I. et al, J. Biol. Chem. 274 (33): 23443-23450, 1999, Hurskainen T. L. et al., J. Biol. Chem. 274 (36): 25555-25563, 1999). Conventionally, MMPs have been considered to mainly cause cartilage destruction, but many reports have documented that the aggrecan fragments found in the joint of osteoarthritis (OA) patients are predominantly the fragments cleaved by aggrecanases. Thus, aggrecanase is also considered to be a significant vicious factor for these disease states.
Aggrecanases have been shown to be involved in cleaving aggrecan, procollagen processing (Colige A et al., Proc. Natl Acad. Sd. USA, 94, 2374-2379, 1997), inflammation (Kuno K. et al., J. Biol. Chem., 272, 556-562, 1997), angiogenesis (Vazquez F. et al., J. Biol. Chem. 1999, 274, 23349-23357) and tumor invasion (Masui T. et al., J. Bio. I Chem., 272, 556-562, 1997).
ADAMTS5 is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The enzyme encoded by this gene contains two C-terminal TS motifs and functions as aggrecanase to cleave aggrecan, a major proteoglycan of cartilage.
Genetically modified mice in which the catalytic domain of ADAMTS5 was deleted are resistant to cartilage destruction in an experimental model of osteoarthritis (Glasson S. S. et al., Nature 434 (7033): 644-648, 2005) and ADAMTS5 is the major aggrecanase in mouse cartilage in a mouse model of inflammatory arthritis (Stanton H. et al., Nature 434 (7033): 648-652, 2005).
Additionally, aggrecanases like MMPs are suggested to be involved in metastasis or tissue infiltration of tumor cells and thus aggrecanase inhibitors are expected to be effective antitumor agents. Furthermore, the following documents disclose, that aggrecanase inhibitors are also effective in the treatment and/or prophylaxis of physiological and/or pathophysiological states, selected from the group consisting of osteoarthritis, traumatic cartilage injuries, pain, allodynia, hyperalgesia, rheumatoid arthritis, joint injury, reactive arthritis, cirrhosis, inflammatory diseases as inflammatory bowel disease, ulceratice colitis, gastritis, psoriasis, eczema and dermatitis, asthma, allergic reaction, chronic obstructive pulmonary disease, fibroid lung, acute respiratory distress (ARDS), lung infection, interstitial pneumonia, atherosclerosis, osteoporosis, age-related macular degeneration, myocardial infarction, corneal ulceration cancer, tumor metastasis and invasion, uncontrolled degradation of the extracellular matrix as in osteoarthritis, central nervous system diseases, abnormal wound healing, multiple sclerosis angiogenesis and restenosis.
The U.S. Pat. Nos. 7,030,242, 6,566,384 and the WO9805635 disclose hydroxamic and carboxylic acid derivatives as aggrecanase and MMP-13 inhibitors for the treatment of osteoarthritis. The US20080096918 discloses cyclic urea derivatives as aggrecanase inhibitors for the treatment of rheumatoid arthritis and osteoarthritis.
The WO2001062750 and the WO2000012478 disclose arylpiperazines as MMP inhibitors for the treatment of various diseases. The WO2009109230 aryl- and heteroarylbenzopyranoneamidino derivatives for the treatment of osteoarthritis and cancer-related pain and the WO2008024922 hydroxyquinoline derivatives for the treatment of metalloproteinase related disorders.
The WO2005058884 discloses cyclopropane compounds as aggrecanase and MMP-13 inhibitors for the treatment of disorders such as rheumatoid arthritis and osteoarthritis, joint injury, reactive arthritis, bone resorption disorder, cancer, asthma, allergic reaction, chronic pulmonary emphysema, fibroid lung, acute respiratory distress (ARDS), lung infection and interstitial pneumonia.
The WO2007008994 and the WO2008058278 disclose glutamate derivatives as aggrecanase inhibitors for the treatment of arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia and periodontal diseases.
The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The aim of the present invention was, in particular, to find novel active compounds and particularly preferably novel ADAMTS5 inhibitors which can be employed for the prevention and treatment of osteoarthritis and have, in particular, high selectivity for ADAMTS5. In addition, the aim was to find novel ADAMTS5 inhibitors which are sufficiently stable, at least on local or intra-articular administration.